Psychedelics Seen Promoting Structural Neural Plasticity

Neurite and dendritic spine growth seen in animal studies

Experiments in cell culture and animal models demonstrated that hallucinogenic drugs affect the structure and function of cortical neurons in ways similar to ketamine, pointing to new treatment approaches for depression, anxiety, addiction, and post-traumatic stress disorder, researchers wrote in Cell Reports.

"The state-of-the-art, prototypical, fast-acting antidepressant is ketamine -- a compound that promotes neural plasticity and repairs circuits involved in mood and anxiety disorders," Olson told MedPage Today. "Our work demonstrates that psychedelics produce comparable effects on neuronal structure and function, providing a potential explanation for why MDMA, psilocybin, and ayahuasca seem to have antidepressant and anxiolytic effects in the clinic."

Depression may be linked to structural changes in brain circuits that stem from neurites retracting, not allowing neurons to connect at the synapse. "One of the hallmarks of depression is that the neurites in the prefrontal cortex -- a key brain region that regulates emotion, mood, and anxiety -- those neurites tend to shrivel up," Olson said in a statement. These changes also appear in anxiety, addiction, and post-traumatic stress disorder.

The anesthetic ketamine has produced rapid antidepressant effects in treatment-resistant populations, leading the FDA to fast-track clinical trials of esketamine, an intranasal antidepressant based on a form of the drug. In theory, the antidepressant properties of ketamine may stem from its tendency to help neurons rewire their connections.

In this study, Olson and colleagues tested psychedelics from the amphetamine, tryptamine, and ergoline drug classes. The psychedelic drugs appeared to mimic the effects of ketamine on neurons in vitro, robustly promoting neurite growth.

These results extended to structural and electrical properties of neurons in both vertebrate and invertebrate animals. Rats treated with a single dose of DMT, a psychedelic compound found in the Amazonian herbal tea ayahuasca, had an increase in the number of dendritic spines similar to that seen with ketamine treatment. DMT has a very short half-life; much of the drug was eliminated in an hour, but it effects on the brain persisted for 24 hours.

The researchers also looked for possible pathways to neural growth that psychedelic drugs might activate. Ketamine's neural plasticity effects appear to depend on brain-derived neurotrophic factor (BDNF); when Olson and his team blocked BDNF signaling in this study, the psychedelic drugs lost their ability to promote neurite growth. BDNF binds to TrkB, which is part of a signaling pathway that includes mTOR. When the researchers experimented by inhibiting mTOR, it also blocked the psychedelic drugs' ability to stimulate neurite growth.

"Although the molecular targets of ketamine and psychedelics are different (NMDA and 5-HT2A receptors, respectively), they appear to cause similar downstream effects on structural plasticity by activating mTOR," they wrote. "This finding is significant because ketamine is known to be addictive whereas many classical psychedelics are not."

Olson thinks that by studying the pathways involved in psychedelic-induced brain changes, researchers may one day identify non-hallucinogenic compounds that could be turned into treatments.

"As the diversity of chemical structures capable of producing ketamine-like plasticity effects continues to grow, so does my hope that we will find a safe and effective fast-acting treatment for depression," he said.

This work was supported by funds from the University of California Davis, an Alfred P. Sloan fellowship, and NIH grants.

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